Background The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) from solid cancers based on clinical, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology presentation. MRI patterns are classified as linear, nodular, both, or neither. Type I LM is defined by positive CSF cytology (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these LM subtypes. Patients and methods We retrospectively assembled data from 254 patients with newly diagnosed LM from solid tumors. Survival curves were derived using the Kaplan-Meier method and compared by Log-rank test. Results Median age at LM diagnosis was 56 years. Typical clinical LM features were noted in 225 patients (89%); 13 patients (5%) were clinically asymptomatic. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 patients (9.5%) and negative in 44 patients (17.5%). Patients with confirmed LM had inferior outcome compared with patients with probable or possible LM (p=0.006). Type I patients had inferior outcome than type II patients (p=0.002). Nodular disease on MRI was a negative prognostic factor in type II LM (p=0.014), but not in type I LM. Administration of either intrathecal pharmacotherapy (p=0.020) or systemic pharmacotherapy (p=0.0004) was associated with improved outcome in type I LM, but not in type II LM. Conclusion The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.

Background Current guidelines do not recommend primary prophylactic anti-epileptic drug (AED) therapy for patients with brain metastases (BM). Yet, subgroups of patients at high seizure risk might still benefit from prophylaxis. Methods We identified 799 patients diagnosed with BM by retrospective screening of our electronic chart system. Candidate risk factors for the development of epilepsy were tested by univariate and multivariate Cox regression models. Results Epilepsy was diagnosed in 226 of 799 patients (28%). Risk factors for epilepsy in non-operated patients were single BM (P = 0.002, hazard ratio [HR] 3.2, 95% CI: 1.5–6.6) and detection of tumoral hemorrhage (P = 0.008, HR 2.5, 95% CI: 1.3–4.9). Preoperative seizures occurred predominantly in patients with supratentorial BM (P = 0.003, HR 20.78, 95% CI: 2.8–153.4) and lung cancer (P = 0.022; HR 2.0, 95% CI: 1.1–3.6). Postoperative seizures were associated with supratentorial localization (P = 0.017, HR 5.8, 95% CI: 1.4–24.3), incomplete resection (P = 0.005, HR 4.6, 95% CI: 1.6–13.1), and by trend for multiple brain surgeries (P = 0.095, HR 1.9, 95% CI: 0.9–4.0). These risk factors were integrated into a predictive score model for postoperative epilepsy (score sum 0–8). A gradual increase of seizure rates along with higher sum score was confirmed post hoc (score 0 = no seizures; score 8 = 48% seizures). Receiver operating characteristic analysis supported diagnostic accuracy (P = 0.00001, area under the curve = 0.75). Conclusions Here we have defined risk profiles for the development of BM-related epilepsy and derived a score which might help to estimate the risk of postoperative seizures and identify individuals at risk who might benefit from primary prophylactic AED therapy.

Glioblastoma is the most frequent malignant primary brain tumor. In a hierarchical tumor model, glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Based on the analysis of patient samples (n = 9) and GSC (n = 3), we performed comparative HLA peptidome profiling against a dataset of normal human tissues. Using this immunopeptidome-centric approach we could clearly delineate a subset of naturally presented, GSC-associated HLA ligands, which might serve as highly specific targets for T cell-based immunotherapy. In total, we identified 17 antigens represented by 41 different HLA ligands showing natural and exclusive presentation both on GSC and patient samples. Importantly, in vitro immunogenicity and antigen-specific target cell killing assays suggest these peptides to be epitopes of functional CD8+ T cell responses, thus rendering them prime candidates for antigen-specific immunotherapy of glioblastoma.

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Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted.

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ObjectiveAn epileptic seizure is the most common clinical manifestation of a primary brain tumor. Due to modern neuroimaging, detailed anatomical information on a brain tumor is available early in the diagnostic process and therefore carries considerable potential in clinical decision making. The goal of this study was to gain a better understanding of the relevance of anatomical tumor characteristics on seizure prevalence and semiology.MethodsWe reviewed prospectively collected clinical and imaging data of all patients operated on a supratentorial intraparenchymal primary brain tumor at our department between January 2009 and December 2016. The effect of tumor histology, anatomical location and white matter infiltration on seizure prevalence and semiology were assessed using uni- and multivariate analyses.ResultsOf 678 included patients, 311 (45.9%) presented with epileptic seizures. Tumor location within the central lobe was associated with higher seizure prevalence (OR 4.67, 95% CI: 1.90–13.3, p = .002), especially within the precentral gyrus or paracentral lobule (100%). Bilateral extension, location within subcortical structures and invasion of deeper white matter sectors were associated with a lower risk (OR 0.45, 95% CI: 0.25–0.78; OR 0.10, 95% CI: 0.04–0.21 and OR 0.39, 95% CI: 0.14–0.96, respectively). Multivariate analysis revealed the impact of a location within the central lobe on seizure risk to be highly significant and more relevant than histopathology (OR: 4.79, 95% CI: 1.82–14.52, p = .003). Seizures due to tumors within the central lobe differed from those of other locations by lower risk of secondary generalization (p < .001).ConclusionsTopographical lobar and gyral location, as well as extent of white matter infiltration impact seizure risk and semiology. This finding may have a high therapeutic potential, for example regarding the use of prophylactic antiepileptic therapy.